Alzheimer's disease and senile dementia of the Alzheimer's type are debilitating neurological disorders with unknown etiologies. A significant quantity of anatomical and histochemical data are available to suggest that cholinergic neurons in the basal forebrain are damaged during the disease process. However, very little is known about the normal physiology of these cells, much less the pathophysiological processes that occur. The paucity of electrophysiological data results from the inability to clearly separate and identify cholinergic nerons. A method has recently been developed to overcome these difficulties using an intracellular double-labelling procedure to specifically identify cholinergic neurons. An in vitro guinea pig brain slice preparation that includes cholinergic nuclei of the basal forebrain has also been developed. Neurons will be studied using intracellular recording, voltage-clamp and quantitative pharmacological techniques. Whole-cell patch-clamping techniques will also be used to study the cellular physiology of acutely dissociated cells. The overall goals of the present proposal are to study the cellular physiology and pharamacology of both cholinergic and noncholinergic neurons located within basal forebrain nuclei. The voltage-dependent conductances, synaptic mechanisms and pharmacological sensitivity of these neurons will be studied. The hypotheses that these cell types are markedly different in terms of cellular properties and in response to potential therapeutic drugs will be tested. Quantitative information concerning the physiology of cholinergic neurons will be a starting point for future pharmacological studies and future cellular models of cholinergic pathophysiology. Long range goals are to study physiological/pharmacological changes in cholinergic neurons under pathophysiological conditons and to develop potential treatments for Alzheimer's disease and senile dementia.